Studies of effects of pyrazofurin and N-(phosphonacety1)-L-aspartate on pyrimidine biosynthesis and on metabolism of pyrimidines and pyrimidine analogs in murine colon tumors and in normal tissues will be continued. Enzymes of pyrimidine metabolism (de novo synthesis and salvage pathways) in murine colon tumors will be further characterized and effects of inhibitors of pyrimidine biosynthesis on these enzyme activities will be examined. Results of these biochemical studies will be applied to the design of combinations of agents for experimental chemotherapy of colon cancer. Results indicate that anguidin inhibits macromolecular synthesis (RNA, DNA, and protein) in murine colon tumors and in tumors and in normal tissues. Anguidin-induced inhibition of synthesis of DNA polymerase may account for observed persistent inhibition of DNA synthesis in anguidin-sensitive colon tumor #36. Effects of anguidin on nucleic acid synthesis and on the levels of closely related enzymes (DNA polymerase, RNA polymerase, ribonucleotide reductase) in murine colon cancers will be examined. Study of effects of anguidin on intracellular deoxyribonucleotide levels also is proposed. Results of these studies will provide a basis for selection of combinations of anguidin with other agents for experimental chemotherapy studies. Proposed work also includes study of effects of MeCCNU (N-(2-chloroethyl)-N'-(trans-4-methylcyclohexyl)-N-nitrosourea) on nucleotide pools, macromolecular synthesis, extent of alkylation of DNA by radioactive MeCCNU, physical effects of alkylation on DNA, and capacity for repair of DNA in responsive and unresponsive colon tumors and in normal tissues.